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Abstract:

The present invention relates to new benzoquinolone inhibitors of VMAT2,
pharmaceutical compositions thereof, and methods of use thereof.
##STR00001##

Claims:

1. A compound of structural Formula II ##STR00156## or a salt or
stereoisomer thereof, wherein: R1-R19 and R21-R39 are
independently selected from the group consisting of hydrogen and
deuterium; at least one of R1-R19 and R21-R39 is
deuterium.

2. The compound of claim 1, wherein said compound is the (+)-alpha
stereoisomer.

3. The compound of claim 1, wherein said compound is the (-)-alpha
stereoisomer.

4. The compound of claim 1, wherein said compound is the (+)-beta
stereoisomer.

5. The compound of claim 1, wherein said compound is the (-)-beta
stereoisomer.

6. The compound as recited in claim 1 wherein at least one of
R1-R19 and R21-R39 independently has deuterium
enrichment of no less than about 10%.

7. The compound as recited in claim 1 wherein at least one of
R1-R19 and R21-R39 independently has deuterium
enrichment of no less than about 50%.

8. The compound as recited in claim 1 wherein at least one of
R1-R19 and R21-R39 independently has deuterium
enrichment of no less than about 90%.

9. The compound as recited in claim 1 wherein at least one of
R1-R19 and R21-R39 independently has deuterium
enrichment of no less than about 98%.

11. The compound as recited in claim 1 wherein said compound has a
structural formula selected from the group consisting of ##STR00294##
##STR00295##

12. The compound as recited in claim 11 wherein each position represented
as D has deuterium enrichment of no less than about 10%.

13. The compound as recited in claim 11 wherein each position represented
as D has deuterium enrichment of no less than about 50%.

14. The compound as recited in claim 11 wherein each position represented
as D has deuterium enrichment of no less than about 90%.

15. The compound as recited in claim 11 wherein each position represented
as D has deuterium enrichment of no less than about 98%.

16. The compound as recited in claim 11 wherein said compound has a
structural formula selected from the group consisting of ##STR00296##
##STR00297##

17. The compound as recited in claim 11 wherein said compound has a
structural formula selected from the group consisting of ##STR00298##
##STR00299##

18. The compound as recited in claim 11 wherein said compound has a
structural formula selected from the group consisting of ##STR00300##
##STR00301##

19. The compound as recited in claim 11 wherein said compound has a
structural formula selected from the group consisting of ##STR00302##
##STR00303##

20. (canceled)

21. (canceled)

22. (canceled)

23. (canceled)

24. (canceled)

25. (canceled)

26. (canceled)

27. A compound of structural Formula III ##STR00304## or a salt or
stereoisomer thereof, wherein: R20 is selected from the group
consisting of --C(O)O-alkyl and --C(O)--C1-6 alkyl, or a group
cleavable under physiological conditions, wherein said alkyl or C1-6
alkyl is optionally substituted with one or more substituents selected
from the group consisting of --NH--C(NH)NH2, --CO2H,
--CO2alkyl, --SH, --C(O)NH2, --NH2, phenyl, --OH,
4-hydroxyphenyl, imidazolyl, and indolyl, and any R20 substituent is
further optionally substituted with deuterium.

28. The compound of claim 27, wherein said compound is the (+)-alpha
stereoisomer.

29. The compound of claim 27, wherein said compound is the (-)-alpha
stereoisomer.

30. The compound of claim 27, wherein said compound is the (+)-beta
stereoisomer.

31. The compound of claim 27, wherein said compound is the (-)-beta
stereoisomer.

32. A pharmaceutical composition comprising a pharmaceutically acceptable
carrier together with a compound as recited in claim 1.

33. A method of treatment of a VMAT2-mediated disorder comprising the
administration, to a patient in need thereof, of a therapeutically
effective amount of a compound as recited in claim 1.

Description:

[0001] This application claims the benefit of priority of U.S. provisional
application No. 61/758,861, filed Jan. 31, 2013, the disclosure of which
is hereby incorporated by reference as if written herein in its entirety.

[0003] NBI-98854 (CAS #1025504-59-9),
(S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyr-
ido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate, is a VMAT2
inhibitor. NBI-98854 is currently under investigation for the treatment
of movement disorders including tardive dyskinesia. WO 2008058261; WO
2011153157; and U.S. Pat. No. 8,039,627. NBI-98854, a valine ester of
(+)-α-dihydrotetrabenazine, in humans is slowly hydrolyzed to
(+)-α-dihydrotetrabenazine which is an active metabolite of
tetrabenazine which is currently used for the treatment of Huntington's
disease. Savani et al., Neurology 2007, 68(10), 797; and Kenney et al.,
Expert Review of Neurotherapeutics 2006, 6(1), 7-17.

##STR00002##

[0004] Dihydrotetrabenazine, formed by hydrolysis of the valine ester of
NBI-98854, is subject to extensive oxidative metabolism, including
O-demethylation of the methoxy groups, as well as hydroxylation of the
isobutyl group (Schwartz et al., Biochem. Pharmacol., 1966, 15, 645-655).
Adverse effects associated potentially associated with the administration
of NBI-98854 include neuroleptic malignant syndrome, drowsiness, fatigue,
nervousness, anxiety, insomnia, agitation, confusion, orthostatic
hypotension, nausea, dizziness, depression, and Parkinsonism.

Deuterium Kinetic Isotope Effect

[0005] In order to eliminate foreign substances such as therapeutic
agents, the animal body expresses various enzymes, such as the cytochrome
P450 enzymes (CYPs), esterases, proteases, reductases,
dehydrogenases, and monoamine oxidases, to react with and convert these
foreign substances to more polar intermediates or metabolites for renal
excretion. Such metabolic reactions frequently involve the oxidation of a
carbon-hydrogen (C--H) bond to either a carbon-oxygen (C--O) or a
carbon-carbon (C--C) π-bond. The resultant metabolites may be stable
or unstable under physiological conditions, and can have substantially
different pharmacokinetic, pharmacodynamic, and acute and long-term
toxicity profiles relative to the parent compounds. For most drugs, such
oxidations are generally rapid and ultimately lead to administration of
multiple or high daily doses.

[0006] The relationship between the activation energy and the rate of
reaction may be quantified by the Arrhenius equation, k=Ae-Eact/RT.
The Arrhenius equation states that, at a given temperature, the rate of a
chemical reaction depends exponentially on the activation energy
(Eact).

[0007] The transition state in a reaction is a short lived state along the
reaction pathway during which the original bonds have stretched to their
limit By definition, the activation energy Eact for a reaction is
the energy required to reach the transition state of that reaction. Once
the transition state is reached, the molecules can either revert to the
original reactants, or form new bonds giving rise to reaction products. A
catalyst facilitates a reaction process by lowering the activation energy
leading to a transition state. Enzymes are examples of biological
catalysts.

[0008] Carbon-hydrogen bond strength is directly proportional to the
absolute value of the ground-state vibrational energy of the bond. This
vibrational energy depends on the mass of the atoms that form the bond,
and increases as the mass of one or both of the atoms making the bond
increases. Since deuterium (D) has twice the mass of protium (1H), a
C-D bond is stronger than the corresponding C-1H bond. If a
C-1H bond is broken during a rate-determining step in a chemical
reaction (i.e. the step with the highest transition state energy), then
substituting a deuterium for that protium will cause a decrease in the
reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope
Effect (DKIE). The magnitude of the DKIE can be expressed as the ratio
between the rates of a given reaction in which a C-1H bond is
broken, and the same reaction where deuterium is substituted for protium.
The DKIE can range from about 1 (no isotope effect) to very large
numbers, such as 50 or more. Substitution of tritium for hydrogen results
in yet a stronger bond than deuterium and gives numerically larger
isotope effects

[0009] Deuterium (2H or D) is a stable and non-radioactive isotope of
hydrogen which has approximately twice the mass of protium (1H), the
most common isotope of hydrogen. Deuterium oxide (D2O or "heavy
water") looks and tastes like H2O, but has different physical
properties.

[0010] When pure D2O is given to rodents, it is readily absorbed. The
quantity of deuterium required to induce toxicity is extremely high. When
about 0-15% of the body water has been replaced by D2O, animals are
healthy but are unable to gain weight as fast as the control (untreated)
group. When about 15-20% of the body water has been replaced with
D2O, the animals become excitable. When about 20-25% of the body
water has been replaced with D2O, the animals become so excitable
that they go into frequent convulsions when stimulated. Skin lesions,
ulcers on the paws and muzzles, and necrosis of the tails appear. The
animals also become very aggressive. When about 30% of the body water has
been replaced with D2O, the animals refuse to eat and become
comatose. Their body weight drops sharply and their metabolic rates drop
far below normal, with death occurring at about 30 to about 35%
replacement with D2O. The effects are reversible unless more than
thirty percent of the previous body weight has been lost due to D2O.
Studies have also shown that the use of D2O can delay the growth of
cancer cells and enhance the cytotoxicity of certain antineoplastic
agents.

[0011] Deuteration of pharmaceuticals to improve pharmacokinetics (PK),
pharmacodynamics (PD), and toxicity profiles has been demonstrated
previously with some classes of drugs. For example, the DKIE was used to
decrease the hepatotoxicity of halothane, presumably by limiting the
production of reactive species such as trifluoroacetyl chloride. However,
this method may not be applicable to all drug classes. For example,
deuterium incorporation can lead to metabolic switching. Metabolic
switching occurs when xenogens, sequestered by Phase I enzymes, bind
transiently and re-bind in a variety of conformations prior to the
chemical reaction (e.g., oxidation). Metabolic switching is enabled by
the relatively vast size of binding pockets in many Phase I enzymes and
the promiscuous nature of many metabolic reactions. Metabolic switching
can lead to different proportions of known metabolites as well as
altogether new metabolites. This new metabolic profile may impart more or
less toxicity. Such pitfalls are non-obvious and are not predictable a
priori for any drug class.

[0012] NBI-98854 is a VMAT2 inhibitor. The carbon-hydrogen bonds of
NBI-98854 contain a naturally occurring distribution of hydrogen
isotopes, namely 1H or protium (about 99.9844%), 2H or
deuterium (about 0.0156%), and 3H or tritium (in the range between
about 0.5 and 67 tritium atoms per 1018 protium atoms). Increased
levels of deuterium incorporation may produce a detectable Deuterium
Kinetic Isotope Effect (DKIE) that could effect the pharmacokinetic,
pharmacologic and/or toxicologic profiles of such NBI-98854 in comparison
with the compound having naturally occurring levels of deuterium.

[0013] Based on discoveries made in our laboratory, as well as considering
the literature, NBI-98854 is metabolized in humans at the isobutyl and
methoxy groups. The current approach has the potential to prevent
metabolism at these sites. Other sites on the molecule may also undergo
transformations leading to metabolites with as-yet-unknown
pharmacology/toxicology. Limiting the production of these metabolites has
the potential to decrease the danger of the administration of such drugs
and may even allow increased dosage and/or increased efficacy. All of
these transformations can occur through polymorphically-expressed
enzymes, exacerbating interpatient variability. Further, some disorders
are best treated when the subject is medicated around the clock or for an
extended period of time. For all of the foregoing reasons, a medicine
with a longer half-life may result in greater efficacy and cost savings.
Various deuteration patterns can be used to (a) reduce or eliminate
unwanted metabolites, (b) increase the half-life of the parent drug, (c)
decrease the number of doses needed to achieve a desired effect, (d)
decrease the amount of a dose needed to achieve a desired effect, (e)
increase the formation of active metabolites, if any are formed, (f)
decrease the production of deleterious metabolites in specific tissues,
and/or (g) create a more effective drug and/or a safer drug for
polypharmacy, whether the polypharmacy be intentional or not. The
deuteration approach has the strong potential to slow the metabolism of
NBI-98854 and attenuate interpatient variability.

[0014] Novel compounds and pharmaceutical compositions, certain of which
have been found to inhibit VMAT2 have been discovered, together with
methods of synthesizing and using the compounds, including methods for
the treatment of VMAT2-mediated disorders in a patient by administering
the compounds.

[0015] In certain embodiments of the present invention, compounds have
structural Formula I:

##STR00003##

or a salt thereof, wherein:

[0016] R1-R19 and R21-R29 are independently selected
from the group consisting of hydrogen and deuterium;

[0017] R20 is selected from the group consisting of hydrogen,
deuterium, --C(O)O-- alkyl and --C(O)--C1-6alkyl, or a group
cleavable under physiological conditions, wherein said alkyl or
C1-6alkyl is optionally substituted with one or more substituents
selected from the group consisting of --NH--C(NH)NH2, --CO2H,
--CO2alkyl, --SH, --C(O)NH2, --NH2, phenyl, --OH,
4-hydroxyphenyl, imidazolyl, and indolyl, and any R20 substituent is
further optionally substituted with deuterium; and

[0018] at least one of R1-R29 is deuterium or contains
deuterium.

[0019] Certain compounds disclosed herein may possess useful VMAT2
inhibiting activity, and may be used in the treatment or prophylaxis of a
disorder in which VMAT2 plays an active role. Thus, certain embodiments
also provide pharmaceutical compositions comprising one or more compounds
disclosed herein together with a pharmaceutically acceptable carrier, as
well as methods of making and using the compounds and compositions.
Certain embodiments provide methods for inhibiting VMAT2. Other
embodiments provide methods for treating a VMAT2-mediated disorder in a
patient in need of such treatment, comprising administering to said
patient a therapeutically effective amount of a compound or composition
according to the present invention. Also provided is the use of certain
compounds disclosed herein for use in the manufacture of a medicament for
the prevention or treatment of a disorder ameliorated by the inhibition
of VMAT2.

[0020] The compounds as disclosed herein may also contain less prevalent
isotopes for other elements, including, but not limited to, 13C or
14C for carbon, 33S, 34S, or 36S for sulfur, 15N
for nitrogen, and 17O or 18O for oxygen.

[0021] In certain embodiments, the compound disclosed herein may expose a
patient to a maximum of about 0.000005% D2O or about 0.00001% DHO,
assuming that all of the C-D bonds in the compound as disclosed herein
are metabolized and released as D2O or DHO. In certain embodiments,
the levels of D2O shown to cause toxicity in animals is much greater
than even the maximum limit of exposure caused by administration of the
deuterium enriched compound as disclosed herein. Thus, in certain
embodiments, the deuterium-enriched compound disclosed herein should not
cause any additional toxicity due to the formation of D2O or DHO
upon drug metabolism.

[0023] In certain embodiments, disclosed herein is a compound of
structural Formula II:

##STR00004##

or a salt or stereoisomer thereof, wherein:

[0024] R1-R19 and R21-R39 are independently selected
from the group consisting of hydrogen and deuterium;

[0025] at least one of R1-R19 and R21-R39 is
deuterium.

[0026] In certain embodiments, the compounds of Formula I have (+)-alpha
stereochemistry.

[0027] In certain embodiments, the compounds of Formula I have (-)-alpha
stereochemistry.

[0028] In further embodiments, the compounds of Formula I have (+)-beta
stereochemistry.

[0029] In further embodiments, the compounds of Formula I have (-)-beta
stereochemistry.

[0030] In certain embodiments of the present invention, compounds have
structural Formula III:

##STR00005##

or a salt or stereoisomer thereof, wherein:

[0031] R20 is selected from the group consisting of --C(O)O-alkyl and
--C(O)--C1-6alkyl, or a group cleavable under physiological
conditions, wherein said alkyl or C1-6alkyl is optionally
substituted with one or more substituents selected from the group
consisting of --NH--C(NH)NH2, --CO2H, --CO2alkyl, --SH,
--C(O)NH2, --NH2, phenyl, --OH, 4-hydroxyphenyl, imidazolyl,
and indolyl, and any R20 substituent is further optionally
substituted with deuterium.

[0032] In yet further embodiments, the compounds of Formula I are a
mixture of alpha and beta stereoisomers. In yet further embodiments, the
ratio of alpha/beta stereoisomers is at least 100:1, at least 50:1, at
least 20:1, at least 10:1, at least 5:1, at least 4:1, at least 3:1, or
at least 2:1. In yet further embodiments, the ratio of beta/alpha
stereoisomers is at least 100:1, at least 50:1, at least 20:1, at least
10:1, at least 5:1, at least 4:1, at least 3:1, or at least 2:1.

[0033] All publications and references cited herein are expressly
incorporated herein by reference in their entirety. However, with respect
to any similar or identical terms found in both the incorporated
publications or references and those explicitly put forth or defined in
this document, then those terms definitions or meanings explicitly put
forth in this document shall control in all respects.

[0036] The term "about," as used herein, is intended to qualify the
numerical values which it modifies, denoting such a value as variable
within a margin of error. When no particular margin of error, such as a
standard deviation to a mean value given in a chart or table of data, is
recited, the term "about" should be understood to mean that range which
would encompass the recited value and the range which would be included
by rounding up or down to that figure as well, taking into account
significant figures.

[0037] When ranges of values are disclosed, and the notation "from n1
. . . to n2" or "n1-n2" is used, where n1 and n2
are the numbers, then unless otherwise specified, this notation is
intended to include the numbers themselves and the range between them.
This range may be integral or continuous between and including the end
values.

[0038] The term "deuterium enrichment" refers to the percentage of
incorporation of deuterium at a given position in a molecule in the place
of hydrogen. For example, deuterium enrichment of 1% at a given position
means that 1% of molecules in a given sample contain deuterium at the
specified position. Because the naturally occurring distribution of
deuterium is about 0.0156%, deuterium enrichment at any position in a
compound synthesized using non-enriched starting materials is about
0.0156%. The deuterium enrichment can be determined using conventional
analytical methods known to one of ordinary skill in the art, including
mass spectrometry and nuclear magnetic resonance spectroscopy.

[0039] The term "is/are deuterium," when used to describe a given position
in a molecule such as R1-R29 or the symbol "D", when used to
represent a given position in a drawing of a molecular structure, means
that the specified position is enriched with deuterium above the
naturally occurring distribution of deuterium. In one embodiment
deuterium enrichment is no less than about 1%, in another no less than
about 5%, in another no less than about 10%, in another no less than
about 20%, in another no less than about 50%, in another no less than
about 70%, in another no less than about 80%, in another no less than
about 90%, or in another no less than about 98% of deuterium at the
specified position.

[0040] The term "isotopic enrichment" refers to the percentage of
incorporation of a less prevalent isotope of an element at a given
position in a molecule in the place of the more prevalent isotope of the
element.

[0041] The term "non-isotopically enriched" refers to a molecule in which
the percentages of the various isotopes are substantially the same as the
naturally occurring percentages.

[0042] Asymmetric centers exist in the compounds disclosed herein. These
centers are designated by the symbols "R" or "S," depending on the
configuration of substituents around the chiral carbon atom. It should be
understood that the invention encompasses all stereochemical isomeric
forms, including diastereomeric, enantiomeric, and epimeric forms, as
well as d-isomers and l-isomers, and mixtures thereof. Individual
stereoisomers of compounds can be prepared synthetically from
commercially available starting materials which contain chiral centers or
by preparation of mixtures of enantiomeric products followed by
separation such as conversion to a mixture of diastereomers followed by
separation or recrystallization, chromatographic techniques, direct
separation of enantiomers on chiral chromatographic columns, or any other
appropriate method known in the art. Starting compounds of particular
stereochemistry are either commercially available or can be made and
resolved by techniques known in the art. Additionally, the compounds
disclosed herein may exist as geometric isomers. The present invention
includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z)
isomers as well as the appropriate mixtures thereof. Additionally,
compounds may exist as tautomers; all tautomeric isomers are provided by
this invention. Additionally, the compounds disclosed herein can exist in
unsolvated as well as solvated forms with pharmaceutically acceptable
solvents such as water, ethanol, and the like. In general, the solvated
forms are considered equivalent to the unsolvated forms.

[0043] The terms "alpha-dihydrotetrabenazine",
"α-dihydrotetrabenazine", or the terms "alpha" or "alpha
stereoisomer" or the symbol "α" as applied to dihydrotetrabenazine
refers to either of the dihydrotetrabenazine stereoisomers having the
structural formulas shown below, or a mixture thereof:

##STR00006##

[0044] The terms "alpha" or "alpha stereoisomer" or the symbol "α"
as applied to a compound of Formula I refers to either of the
stereoisomers of compounds of Formula I shown below, or a mixture
thereof:

##STR00007##

[0045] The terms "beta-dihydrotetrabenazine",
"β-dihydrotetrabenazine", or the terms "beta" or "beta stereoisomer"
or the symbol "β" as applied to dihydrotetrabenazine refers to
either of the dihydrotetrabenazine stereoisomers having the structural
formulas shown below, or a mixture thereof:

##STR00008##

[0046] The terms "beta" or "beta stereoisomer" or the symbol "β" as
applied to a compound of Formula I refers to either of the stereoisomers
of compounds of Formula I shown below, or a mixture thereof:

##STR00009##

[0047] The term "bond" refers to a covalent linkage between two atoms, or
two moieties when the atoms joined by the bond are considered to be part
of larger substructure. A bond may be single, double, or triple unless
otherwise specified. A dashed line between two atoms in a drawing of a
molecule indicates that an additional bond may be present or absent at
that position.

[0048] The term "disorder" as used herein is intended to be generally
synonymous, and is used interchangeably with, the terms "disease",
"syndrome", and "condition" (as in medical condition), in that all
reflect an abnormal condition of the human or animal body or of one of
its parts that impairs normal functioning, is typically manifested by
distinguishing signs and symptoms.

[0049] The terms "treat," "treating," and "treatment" are meant to include
alleviating or abrogating a disorder or one or more of the symptoms
associated with a disorder; or alleviating or eradicating the cause(s) of
the disorder itself. As used herein, reference to "treatment" of a
disorder is intended to include prevention. The terms "prevent,"
"preventing," and "prevention" refer to a method of delaying or
precluding the onset of a disorder; and/or its attendant symptoms,
barring a subject from acquiring a disorder or reducing a subject's risk
of acquiring a disorder.

[0050] The term "therapeutically effective amount" refers to the amount of
a compound that, when administered, is sufficient to prevent development
of, or alleviate to some extent, one or more of the symptoms of the
disorder being treated. The term "therapeutically effective amount" also
refers to the amount of a compound that is sufficient to elicit the
biological or medical response of a cell, tissue, system, animal, or
human that is being sought by a researcher, veterinarian, medical doctor,
or clinician.

[0051] The term "subject" refers to an animal, including, but not limited
to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like),
rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like),
lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and
the like. The terms "subject" and "patient" are used interchangeably
herein in reference, for example, to a mammalian subject, such as a human
patient.

[0052] The term "combination therapy" means the administration of two or
more therapeutic agents to treat a therapeutic disorder described in the
present disclosure. Such administration encompasses co-administration of
these therapeutic agents in a substantially simultaneous manner, such as
in a single capsule having a fixed ratio of active ingredients or in
multiple, separate capsules for each active ingredient. In addition, such
administration also encompasses use of each type of therapeutic agent in
a sequential manner. In either case, the treatment regimen will provide
beneficial effects of the drug combination in treating the disorders
described herein.

[0053] The term "stereotyped" refers to a repeated behavior that appears
repetitively with slight variation or, less commonly, as a complex series
of movements.

[0054] The term "oppositional defiant disorder" or "ODD," refers to a
psychiatric disorder characterized by aggressiveness and a tendency to
purposely bother and irritate others. According to diagnostic guidelines,
oppositional defiant disorder is characterized by a repeating pattern of
defiant, disobedient, hostile and negative behavior toward authority
figures. In one embodiment, oppositional defiant disorder occurs for at
least six months. In one embodiment, oppositional defiant disorder occurs
more often than other children at the same developmental level. In one
embodiment, in order to be diagnosed with oppositional defiant disorder,
children must exhibit four or more of the following symptoms: (1) often
loses temper, (2) often argues with adults, (3) often actively defies or
refuses to comply with adults' requests or rules, (4) often blames others
for his or her misbehavior or mistakes, (5) is often touchy or easily
annoyed by others, (6) is often angry and resentful, or (7) is often
spiteful and vindictive. In one embodiment, behaviors that can be
expected from a child with oppositional defiant disorder include: (1)
arguing, (2) claiming not to care about losing privileges as a
consequence to negative behavior, (3) continually placing blame on
others, (4) not accepting responsibility for actions, (5) ignoring
directives, (6) playing adults against each other (e.g. parent and
teacher), (7) refusing to go to "time out," (8) resistance to directions,
(9) stubbornness, (10) testing limits, and (11) unwillingness to
compromise, give in, or negotiate with adults or peers.

[0055] The term "Parkinson's disease levodopa-induced dyskinesia,"
"levodopa-induced dyskinesia," or "LID" refers to an abnormal muscular
activity disorder characterized by either disordered or excessive
movement (referred to as "hyperkinesia" or "dyskinesia"), or slowness, or
a lack of movement (referred to as "hypokinesia," "bradykinesia," or
"akinesia"). Based on their relationship with levodopa dosing,
levodopa-induced dyskinesias are classified as peak-dose, diphasic, off
state, on state, and yo yo dyskinesias. Peak-dose dyskinesias are the
most common forms of LID and are related to peak plasma (and possibly
high striatal) levels of levodopa. They involve the head, trunk, and
limbs, and sometimes respiratory muscles. Dose reduction can ameliorate
them, frequently at the cost of deterioration of parkinsonism. Peak-dose
dyskinesias are usually choreiform, though in the later stages dystonia
can superimpose. Diphasic dyskinesias develop when plasma levodopa levels
are rising or falling, but not with the peak levels. They are also called
D-I-D (dyskinesia-improvement-dyskinesia). D-I-D are commonly dystonic in
nature, though chorea or mixed pattern may occur. They do not respond to
levodopa dose reduction and may rather improve with high dose of
levodopa. "Off" state dystonias occur when plasma levodopa levels are low
(for example, in the morning). They are usually pure dystonia occurring
as painful spasms in one foot. They respond to levodopa therapy. Rare
forms of LID include "on" state dystonias (occurring during higher levels
of levodopa) and yo-yo dyskinesia (completely unpredictable pattern).

[0056] The term "VMAT2" refers to vesicular monoamine transporter 2, an
integral membrane protein that acts to transport monoamines--particularly
neurotransmitters such as dopamine, norepinephrine, serotonin, and
histamine--from cellular cytosol into synaptic vesicles.

[0057] The term "VMAT2-mediated disorder," refers to a disorder that is
characterized by abnormal VMAT2 activity, or VMAT2 activity that, when
modulated, leads to the amelioration of other abnormal biological
processes. A VMAT2-mediated disorder may be completely or partially
mediated by modulating VMAT2. In particular, a VMAT2-mediated disorder is
one in which inhibition of VMAT2 results in some effect on the underlying
disorder e.g., administration of a VMAT2 inhibitor results in some
improvement in at least some of the patients being treated.

[0058] The term "VMAT2 inhibitor", "inhibit VMAT2", or "inhibition of
VMAT2" refers to the ability of a compound disclosed herein to alter the
function of VMAT2. A VMAT2 inhibitor may block or reduce the activity of
VMAT2 by forming a reversible or irreversible covalent bond between the
inhibitor and VMAT2 or through formation of a noncovalently bound
complex. Such inhibition may be manifest only in particular cell types or
may be contingent on a particular biological event. The term "VMAT2
inhibitor", "inhibit VMAT2", or "inhibition of VMAT2" also refers to
altering the function of VMAT2 by decreasing the probability that a
complex forms between a VMAT2 and a natural substrate. In some
embodiments, modulation of the VMAT2 may be assessed using the method
described in WO 2005077946; WO 2008/058261; EP 1716145; Kilbourn et al.,
European Journal of Pharmacology 1995, (278), 249-252; Lee et al., J.
Med. Chem., 1996, (39), 191-196; Scherman et al., Journal of
Neurochemistry 1988, 50(4), 1131-36; Kilbourn et al., Synapse 2002,
43(3), 188-194; Kilbourn et al., European Journal of Pharmacology 1997,
331(2-3), 161-68; and Erickson et al., Journal of Molecular Neuroscience
1995, 6(4), 277-87.

[0059] The term "therapeutically acceptable" refers to those compounds (or
salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable
for use in contact with the tissues of patients without excessive
toxicity, irritation, allergic response, immunogenecity, are commensurate
with a reasonable benefit/risk ratio, and are effective for their
intended use.

[0060] The term "pharmaceutically acceptable carrier," "pharmaceutically
acceptable excipient," "physiologically acceptable carrier," or
"physiologically acceptable excipient" refers to a
pharmaceutically-acceptable material, composition, or vehicle, such as a
liquid or solid filler, diluent, excipient, solvent, or encapsulating
material. Each component must be "pharmaceutically acceptable" in the
sense of being compatible with the other ingredients of a pharmaceutical
formulation. It must also be suitable for use in contact with the tissue
or organ of humans and animals without excessive toxicity, irritation,
allergic response, immunogenecity, or other problems or complications,
commensurate with a reasonable benefit/risk ratio. See, Remington: The
Science and Practice of Pharmacy, 21st Edition; Lippincott Williams &
Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,
5th Edition; Rowe et al., Eds., The Pharmaceutical Press and the American
Pharmaceutical Association: 2005; and Handbook of Pharmaceutical
Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007;
Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC:
Boca Raton, Fla., 2004).

[0061] The terms "active ingredient," "active compound," and "active
substance" refer to a compound, which is administered, alone or in
combination with one or more pharmaceutically acceptable excipients or
carriers, to a subject for treating, preventing, or ameliorating one or
more symptoms of a disorder.

[0062] The terms "drug," "therapeutic agent," and "chemotherapeutic agent"
refer to a compound, or a pharmaceutical composition thereof, which is
administered to a subject for treating, preventing, or ameliorating one
or more symptoms of a disorder.

[0063] The term "release controlling excipient" refers to an excipient
whose primary function is to modify the duration or place of release of
the active substance from a dosage form as compared with a conventional
immediate release dosage form.

[0064] The term "nonrelease controlling excipient" refers to an excipient
whose primary function do not include modifying the duration or place of
release of the active substance from a dosage form as compared with a
conventional immediate release dosage form.

[0066] The compounds disclosed herein can exist as therapeutically
acceptable salts. The term "therapeutically acceptable salt," as used
herein, represents salts or zwitterionic forms of the compounds disclosed
herein which are therapeutically acceptable as defined herein. The salts
can be prepared during the final isolation and purification of the
compounds or separately by reacting the appropriate compound with a
suitable acid or base. Therapeutically acceptable salts include acid and
basic addition salts. For a more complete discussion of the preparation
and selection of salts, refer to "Handbook of Pharmaceutical Salts,
Properties, and Use," Stah and Wermuth, Ed.; (Wiley-VCH and VHCA, Zurich,
2002) and Berge et al., J. Pharm. Sci. 1977, 66, 1-19.

[0069] While it may be possible for the compounds of the subject invention
to be administered as the raw chemical, it is also possible to present
them as a pharmaceutical composition. Accordingly, provided herein are
pharmaceutical compositions which comprise one or more of certain
compounds disclosed herein, or one or more pharmaceutically acceptable
salts, prodrugs, or solvates thereof, together with one or more
pharmaceutically acceptable carriers thereof and optionally one or more
other therapeutic ingredients. Proper formulation is dependent upon the
route of administration chosen. Any of the well-known techniques,
carriers, and excipients may be used as suitable and as understood in the
art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical
compositions disclosed herein may be manufactured in any manner known in
the art, e.g., by means of conventional mixing, dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping or
compression processes. The pharmaceutical compositions may also be
formulated as a modified release dosage form, including delayed-,
extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-
and fast-, targeted-, programmed-release, and gastric retention dosage
forms. These dosage forms can be prepared according to conventional
methods and techniques known to those skilled in the art (see, Remington:
The Science and Practice of Pharmacy, supra; Modified-Release Drug
Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical
Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126).

[0070] The compositions include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous,
intraarticular, and intramedullary), intraperitoneal, transmucosal,
transdermal, rectal and topical (including dermal, buccal, sublingual and
intraocular) administration although the most suitable route may depend
upon for example the condition and disorder of the recipient. The
compositions may conveniently be presented in unit dosage form and may be
prepared by any of the methods well known in the art of pharmacy.
Typically, these methods include the step of bringing into association a
compound of the subject invention or a pharmaceutically salt, prodrug, or
solvate thereof ("active ingredient") with the carrier which constitutes
one or more accessory ingredients. In general, the compositions are
prepared by uniformly and intimately bringing into association the active
ingredient with liquid carriers or finely divided solid carriers or both
and then, if necessary, shaping the product into the desired formulation.

[0071] Formulations of the compounds disclosed herein suitable for oral
administration may be presented as discrete units such as capsules,
cachets or tablets each containing a predetermined amount of the active
ingredient; as a powder or granules; as a solution or a suspension in an
aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient may
also be presented as a bolus, electuary or paste.

[0072] Pharmaceutical preparations which can be used orally include
tablets, push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
Tablets may be made by compression or molding, optionally with one or
more accessory ingredients. Compressed tablets may be prepared by
compressing in a suitable machine the active ingredient in a free-flowing
form such as a powder or granules, optionally mixed with binders, inert
diluents, or lubricating, surface active or dispersing agents. Molded
tablets may be made by molding in a suitable machine a mixture of the
powdered compound moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and may be formulated so as to provide
slow or controlled release of the active ingredient therein. All
formulations for oral administration should be in dosages suitable for
such administration. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such as
starches, and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may be
dissolved or suspended in suitable liquids, such as fatty oils, liquid
paraffin, or liquid polyethylene glycols. In addition, stabilizers may be
added. Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solutions, and
suitable organic solvents or solvent mixtures. Dyestuffs or pigments may
be added to the tablets or dragee coatings for identification or to
characterize different combinations of active compound doses.

[0073] The compounds may be formulated for parenteral administration by
injection, e.g., by bolus injection or continuous infusion. Formulations
for injection may be presented in unit dosage form, e.g., in ampoules or
in multi-dose containers, with an added preservative. The compositions
may take such forms as suspensions, solutions or emulsions in oily or
aqueous vehicles, and may contain formulatory agents such as suspending,
stabilizing and/or dispersing agents. The formulations may be presented
in unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in powder form or in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile liquid
carrier, for example, saline or sterile pyrogen-free water, immediately
prior to use. Extemporaneous injection solutions and suspensions may be
prepared from sterile powders, granules and tablets of the kind
previously described.

[0074] Formulations for parenteral administration include aqueous and
non-aqueous (oily) sterile injection solutions of the active compounds
which may contain antioxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended recipient;
and aqueous and non-aqueous sterile suspensions which may include
suspending agents and thickening agents. Suitable lipophilic solvents or
vehicles include fatty oils such as sesame oil, or synthetic fatty acid
esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous
injection suspensions may contain substances which increase the viscosity
of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or
dextran. Optionally, the suspension may also contain suitable stabilizers
or agents which increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions.

[0075] In addition to the formulations described previously, the compounds
may also be formulated as a depot preparation. Such long acting
formulations may be administered by implantation (for example
subcutaneously or intramuscularly) or by intramuscular injection. Thus,
for example, the compounds may be formulated with suitable polymeric or
hydrophobic materials (for example as an emulsion in an acceptable oil)
or ion exchange resins, or as sparingly soluble derivatives, for example,
as a sparingly soluble salt.

[0076] For buccal or sublingual administration, the compositions may take
the form of tablets, lozenges, pastilles, or gels formulated in
conventional manner. Such compositions may comprise the active ingredient
in a flavored basis such as sucrose and acacia or tragacanth.

[0077] The compounds may also be formulated in rectal compositions such as
suppositories or retention enemas, e.g., containing conventional
suppository bases such as cocoa butter, polyethylene glycol, or other
glycerides.

[0078] Certain compounds disclosed herein may be administered topically,
that is by non-systemic administration. This includes the application of
a compound disclosed herein externally to the epidermis or the buccal
cavity and the instillation of such a compound into the ear, eye and
nose, such that the compound does not significantly enter the blood
stream. In contrast, systemic administration refers to oral, intravenous,
intraperitoneal and intramuscular administration.

[0079] Formulations suitable for topical administration include liquid or
semi-liquid preparations suitable for penetration through the skin to the
site of inflammation such as gels, liniments, lotions, creams, ointments
or pastes, and drops suitable for administration to the eye, ear or nose.

[0080] For administration by inhalation, compounds may be delivered from
an insufflator, nebulizer pressurized packs or other convenient means of
delivering an aerosol spray. Pressurized packs may comprise a suitable
propellant such as dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the
case of a pressurized aerosol, the dosage unit may be determined by
providing a valve to deliver a metered amount.

[0081] Alternatively, for administration by inhalation or insufflation,
the compounds according to the invention may take the form of a dry
powder composition, for example a powder mix of the compound and a
suitable powder base such as lactose or starch. The powder composition
may be presented in unit dosage form, in for example, capsules,
cartridges, gelatin or blister packs from which the powder may be
administered with the aid of an inhalator or insufflator.

[0082] Preferred unit dosage formulations are those containing an
effective dose, as herein below recited, or an appropriate fraction
thereof, of the active ingredient.

[0083] Compounds may be administered orally or via injection at a dose of
from 0.1 to 500 mg/kg per day. The dose range for adult humans is
generally from 5 mg to 2 g/day. Tablets or other forms of presentation
provided in discrete units may conveniently contain an amount of one or
more compounds which is effective at such dosage or as a multiple of the
same, for instance, units containing 5 mg to 500 mg, usually around 10 mg
to 200 mg.

[0084] The amount of active ingredient that may be combined with the
carrier materials to produce a single dosage form will vary depending
upon the host treated and the particular mode of administration.

[0085] The compounds can be administered in various modes, e.g. orally,
topically, or by injection. The precise amount of compound administered
to a patient will be the responsibility of the attendant physician. The
specific dose level for any particular patient will depend upon a variety
of factors including the activity of the specific compound employed, the
age, body weight, general health, sex, diets, time of administration,
route of administration, rate of excretion, drug combination, the precise
disorder being treated, and the severity of the disorder being treated.
Also, the route of administration may vary depending on the disorder and
its severity.

[0086] In the case wherein the patient's condition does not improve, upon
the doctor's discretion the administration of the compounds may be
administered chronically, that is, for an extended period of time,
including throughout the duration of the patient's life in order to
ameliorate or otherwise control or limit the symptoms of the patient's
disorder.

[0087] In the case wherein the patient's status does improve, upon the
doctor's discretion the administration of the compounds may be given
continuously or temporarily suspended for a certain length of time (i.e.,
a "drug holiday").

[0088] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the dosage
or the frequency of administration, or both, can be reduced, as a
function of the symptoms, to a level at which the improved disorder is
retained. Patients can, however, require intermittent treatment on a
long-term basis upon any recurrence of symptoms.

[0089] Disclosed herein are methods of treating a VMAT2-mediated disorder
comprising administering to a subject having or suspected to have such a
disorder, a therapeutically effective amount of a compound as disclosed
herein or a pharmaceutically acceptable salt, solvate, or prodrug
thereof.

[0092] In certain embodiments, a method of treating a VMAT2-mediated
disorder comprises administering to the subject a therapeutically
effective amount of a compound of as disclosed herein, or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to
affect: (1) decreased inter-individual variation in plasma levels of the
compound or a metabolite thereof; (2) increased average plasma levels of
the compound or decreased average plasma levels of at least one
metabolite of the compound per dosage unit; (3) decreased inhibition of,
and/or metabolism by at least one cytochrome P450 or monoamine
oxidase isoform in the subject; (4) decreased metabolism via at least one
polymorphically-expressed cytochrome P450 isoform in the subject;
(5) at least one statistically-significantly improved disorder-control
and/or disorder-eradication endpoint; (6) an improved clinical effect
during the treatment of the disorder, (7) prevention of recurrence, or
delay of decline or appearance, of abnormal alimentary or hepatic
parameters as the primary clinical benefit, or (8) reduction or
elimination of deleterious changes in any diagnostic hepatobiliary
function endpoints, as compared to the corresponding non-isotopically
enriched compound.

[0093] In certain embodiments, inter-individual variation in plasma levels
of the compounds as disclosed herein, or metabolites thereof, is
decreased; average plasma levels of the compound as disclosed herein are
increased; average plasma levels of a metabolite of the compound as
disclosed herein are decreased; inhibition of a cytochrome P450 or
monoamine oxidase isoform by a compound as disclosed herein is decreased;
or metabolism of the compound as disclosed herein by at least one
polymorphically-expressed cytochrome P450 isoform is decreased; by
greater than about 5%, greater than about 10%, greater than about 20%,
greater than about 30%, greater than about 40%, or by greater than about
50% as compared to the corresponding non-isotopically enriched compound.

[0096] Examples of monoamine oxidase isoforms in a mammalian subject
include, but are not limited to, MAOA, and MAOB.

[0097] The inhibition of the cytochrome P450 isoform is measured by
the method of Ko et al. (British Journal of Clinical Pharmacology, 2000,
49, 343-351). The inhibition of the MAOA isoform is measured by the
method of Weyler et al. (J. Biol Chem. 1985, 260, 13199-13207). The
inhibition of the MAOB isoform is measured by the method of
Uebelhack et al. (Pharmacopsychiatry, 1998, 31, 187-192).

[0098] Examples of polymorphically-expressed cytochrome P450 isoforms
in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9,
CYP2C19, and CYP2D6.

[0099] The metabolic activities of liver microsomes, cytochrome P450
isoforms, and monoamine oxidase isoforms are measured by the methods
described herein.

[0100] Examples of improved disorder-control and/or disorder-eradication
endpoints, or improved clinical effects include, but are not limited to,
change from baseline in the chorea score of the Unified Huntington's
Disease Rating Scale (UHDRS).

[0129] Besides being useful for human treatment, certain compounds and
formulations disclosed herein may also be useful for veterinary treatment
of companion animals, exotic animals and farm animals, including mammals,
rodents, and the like. More preferred animals include horses, dogs, and
cats.

Combination Therapy

[0130] The compounds disclosed herein may also be combined or used in
combination with other agents useful in the treatment of VMAT2-mediated
disorders. Or, by way of example only, the therapeutic effectiveness of
one of the compounds described herein may be enhanced by administration
of an adjuvant (i.e., by itself the adjuvant may only have minimal
therapeutic benefit, but in combination with another therapeutic agent,
the overall therapeutic benefit to the patient is enhanced).

[0131] Such other agents, adjuvants, or drugs, may be administered, by a
route and in an amount commonly used therefor, simultaneously or
sequentially with a compound as disclosed herein. When a compound as
disclosed herein is used contemporaneously with one or more other drugs,
a pharmaceutical composition containing such other drugs in addition to
the compound disclosed herein may be utilized, but is not required.

[0132] In certain embodiments, the compounds disclosed herein can be
combined with one or more dopamine precursors, including, but not limited
to, levodopa.

[0133] In certain embodiments, the compounds disclosed herein can be
combined with one or more DOPA decarboxylase inhibitors, including, but
not limited to, carbidopa.

[0134] In certain embodiments, the compounds disclosed herein can be
combined with one or more catechol-O-methyl transferase (COMT)
inhibitors, including, but not limited to, entacapone and tolcapone.

[0135] In certain embodiments, the compounds disclosed herein can be
combined with one or more dopamine receptor agonists, including, but not
limited to, apomorphine, bromocriptine, ropinirole, and pramipexole.

[0136] In certain embodiments, the compounds disclosed herein can be
combined with one or more neuroprotective agents, including, but not
limited to, selegeline and riluzole.

[0137] In certain embodiments, the compounds disclosed herein can be
combined with one or more NMDA antagonists, including, but not limited
to, amantidine.

[0142] Thus, in another aspect, certain embodiments provide methods for
treating VMAT2-mediated disorders in a human or animal subject in need of
such treatment comprising administering to said subject an amount of a
compound disclosed herein effective to reduce or prevent said disorder in
the subject, in combination with at least one additional agent for the
treatment of said disorder that is known in the art. In a related aspect,
certain embodiments provide therapeutic compositions comprising at least
one compound disclosed herein in combination with one or more additional
agents for the treatment of VMAT2-mediated disorders.

General Synthetic Methods for Preparing Compounds

[0143] Isotopic hydrogen can be introduced into a compound as disclosed
herein by synthetic techniques that employ deuterated reagents, whereby
incorporation rates are pre-determined; and/or by exchange techniques,
wherein incorporation rates are determined by equilibrium conditions, and
may be highly variable depending on the reaction conditions. Synthetic
techniques, where tritium or deuterium is directly and specifically
inserted by tritiated or deuterated reagents of known isotopic content,
may yield high tritium or deuterium abundance, but can be limited by the
chemistry required. Exchange techniques, on the other hand, may yield
lower tritium or deuterium incorporation, often with the isotope being
distributed over many sites on the molecule.

[0145] The following schemes can be used to practice the present
invention. Any position shown as hydrogen may optionally be replaced with
deuterium.

##STR00010##

[0146] Compound 1 is reacted with compound 2 in an appropriate solvent,
such as nitromethane, in the presence of an appropriate acid, such as
ammonium acetate, at an elevated temperature to give compound 3. Compound
3 is reacted with compound 4 in the presence of an appropriate base, such
as potassium carbonate, in an appropriate solvent, such as
N,N-dimethylformamide, at an elevated temperature to afford compound 5.
Compound 5 is reacted with an appropriate reducing reagent, such as
lithium aluminum hydride, in an appropriate solvent, such as
tetrahydrofuran, at an elevated temperature to give compound 6. Compound
6 is reacted with compound 7 in the presence of an appropriate acid, such
as trifluoroacetic acid, in an appropriate solvent, such as acetic acid,
at an elevated temperature to give compound 8. Compound 9 is reacted with
compound 10 and compound 11, in an appropriate solvent, such as methanol,
at an elevated temperature to afford compound 12. Compound 12 is reacted
with an appropriate methylating agent, such as methyl iodide, in an
appropriate solvent, such as ethyl acetate, to give compound 13. Compound
8 is reacted with compound 13 in an appropriate solvent, such as ethanol,
at an elevated temperature to give compound 14. Compound 14 is reacted
with an appropriate reducing agent, such as sodium borohydride, in an
appropriate solvent, such as methanol, to give compound 15 of Formula I.

[0147] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme I, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R1-R6, compound 4 with the
corresponding deuterium substitutions can be used. To introduce deuterium
at one or more positions of R7-R9, compound 1 with the
corresponding deuterium substitutions can be used. To introduce deuterium
at one or more positions of R10 and R12, lithium aluminum
deuteride can be used. To introduce deuterium at R11, compound 2
with the corresponding deuterium substitution can be used. To introduce
deuterium at one or more positions of R13-R14, compound 10 with
the corresponding deuterium substitutions can be used. To introduce
deuterium at R15, compound 7 with the corresponding deuterium
substitution can be used. To introduce deuterium at one or more positions
of R16-R17, R19, and R21-R29, compound 9 with
the corresponding deuterium substitutions can be used. To introduce
deuterium at R18, sodium borodeuteride can be used.

[0148] Deuterium can be incorporated to various positions having an
exchangeable proton, such as the hydroxyl O--H, via proton-deuterium
equilibrium exchange. For example, to introduce deuterium at R20,
this proton may be replaced with deuterium selectively or non-selectively
through a proton-deuterium exchange method known in the art.

##STR00011##

[0149] Compound 14 is reacted with an appropriate reducing agent, such as
lithium tri-sec-butyl borohydride, in an appropriate solvent, such as
ethanol, to give a mixture of compounds 16 and 17 of Formula I. Compounds
16 and 17 are reacted with an appropriate dehydrating reagent, such as
phosphorous pentachloride, in an appropriate solvent, such as
dichloromethane to afford a mixture of compounds 18 and 19. Compounds 18
and 19 are reacted with an appropriate hydroborating reagent, such as
borane-tetrahydrofuran complex, in an appropriate solvent, such as
tetrahydrofuran, then oxidized with a mixture of sodium hydroxide and
hydrogen peroxide, to give compounds 20 and 21 of Formula I. Mixtures of
compounds 16 and 17 or 20 and 21 can be separated by chiral preparative
chromatography of through the preparation of Mosher's esters (wherein the
mixture is treated with R-(+)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic
acid, an appropriate chlorinating agent, such as oxalyl chloride, and an
appropriate base, such as 4-dimethylaminopyridine, in an appropriate
solvent, such as dichloromethane, to give an epimeric mixture of
R-(+)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate esters), which can be
isolated via chromatography and then converted to the desired alcohol via
hydrolysis (the Mosher's esters are treated with an appropriate base,
such as sodium hydroxide, in an appropriate solvent, such as methanol, to
give the desired compounds of Formula I).

[0150] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme II, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R1-R17 and R21-R29,
compound 14 with the corresponding deuterium substitutions can be used.
To introduce deuterium at R18, lithium tri-sec-butyl borodeuteride
can be used. To introduce deuterium at R19, trideuteroborane can be
used.

[0151] Deuterium can be incorporated to various positions having an
exchangeable proton, such as the hydroxyl O--H, via proton-deuterium
equilibrium exchange. For example, to introduce deuterium at R20,
this proton may be replaced with deuterium selectively or non-selectively
through a proton-deuterium exchange method known in the art.

##STR00012##

[0152] Compounds 18 and 19 (prepared as shown in Scheme II) are reacted
with an appropriate peroxidizing agent, such as m-chloroperbenzoic acid,
in the presence of an appropriate acid, such as perchloric acid, in an
appropriate solvent, such as methanol, to give compounds 22 and 23.
Compounds 22 and 23 are reacted with an appropriate reducing agent, such
as borane-tetrahydrofuran complex, in an appropriate solvent, such as
tetrahydrofuran, then hydrolyzed with a mixture of sodium hydroxide and
hydrogen peroxide, to give compounds 24 and 25 of Formula I. Mixtures of
compounds 24 and 25 can be separated by chiral preparative chromatography
of through the preparation of Mosher's esters (wherein the mixture is
treated with R-(+)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, an
appropriate chlorinating agent, such as oxalyl chloride, and an
appropriate base, such as 4-dimethylaminopyridine, in an appropriate
solvent, such as dichloromethane, to give an epimeric mixture of
R-(+)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate esters), which can be
isolated via chromatography and then converted to the desired alcohol via
hydrolysis (the Mosher's esters are treated with an appropriate base,
such as sodium hydroxide, in an appropriate solvent, such as methanol, to
give the desired compounds of Formula I).

[0153] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme III, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R1-R18 and R21-R29,
compounds 18 and 19 with the corresponding deuterium substitutions can be
used. To introduce deuterium at R19, trideuteroborane can be used.

[0154] Deuterium can be incorporated to various positions having an
exchangeable proton, such as the hydroxyl O--H, via proton-deuterium
equilibrium exchange. For example, to introduce deuterium at R20,
this proton may be replaced with deuterium selectively or non-selectively
through a proton-deuterium exchange method known in the art.

##STR00013##

[0155] Compound 15 is reacted with an appropriate phosgene equivalent,
such as triphosgene, in an appropriate solvent, such as dichloromethane,
to give compound 26. Compound 26 is reacted with an appropriate alcohol,
such as compound 27, in the presence of an appropriate base, such as
4-dimethylaminopyridine, to give compound 28 of Formula I (where R22
is --C(O))-- alkyl).

[0156] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme IV, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R1-R19 and R21-R29,
compound 16 with the corresponding deuterium substitutions can be used.
To introduce deuterium at R20, compound 27 with the corresponding
deuterium substitutions can be used.

##STR00014##

[0157] Compound 29 is reacted with an appropriate protecting agent, such
as di-tert-butyl dicarbonate, in an appropriate solvent, such as a
mixture of tetrahydrofuran and water, in the presence of an appropriate
base, such as sodium carbonate, to give compound 30. Compound 30 is
reacted with compound 4 in the presence of an appropriate base, such as
potassium carbonate, in the presence of an appropriate catalyst, such as
18-crown-6, in an appropriate solvent, such as acetone, to afford
compound 31. Compound 31 is reacted with an appropriate deprotecting
agent, such as hydrogen chloride, in an appropriate solvent, such as
ethyl acetate, to give compound 6. Compound 6 is reacted with compound 32
at an elevated temperature to give compound 33. Compound 33 is reacted
with an appropriate dehydrating agent, such as phosphorous oxychloride,
at an elevated temperature to afford compound 8. Compound 8 is reacted
with compound 13 in an appropriate solvent, such as methanol, at an
elevated temperature to give compound 14.

[0158] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme V, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R1-R6, compound 4 with the
corresponding deuterium substitutions can be used. To introduce deuterium
at one or more positions of R7-R12, compound 29 with the
corresponding deuterium substitutions can be used. To introduce deuterium
at R15, compound 32 with the corresponding deuterium substitution
can be used. To introduce deuterium at one or more positions of
R13-R14, R16-R17, R19, and R21-R29,
compound 13 with the corresponding deuterium substitutions can be used.

##STR00015##

[0159] Compound 9 is reacted with compound 11 and compound 34
(paraformaldehyde and/or formaldehyde) in an appropriate solvent, such as
ethanol, in the presence of an appropriate acid, such as hydrochloric
acid, at an elevated temperature to give compound 12. Compound 12 is
reacted with an appropriate methylating agent, such as methyl iodide, in
an appropriate solvent, such as ethyl acetate, to give compound 13.
Compound 8 is reacted with compound 13 in an appropriate solvent, such as
dichloromethane, to give compound 13.

[0160] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme VI, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R13-R14, compound 10 with the
corresponding deuterium substitutions can be used. To introduce deuterium
at one or more positions of R16-R17, R19, and
R21-R29, compound 9 with the corresponding deuterium
substitutions can be used.

##STR00016##

[0161] Compound 35 is reacted with compound 36 in an appropriate solvent,
such as tetrahydrofuran, in the presence of an appropriate catalyst, such
as cuprous iodide, and an appropriate co-solvent, such as
hexamethylphosphorous triamide, then reacted with an appropriate
protecting agent, such as trimethylsilyl chloride, and an appropriate
base, such as triethylamine, to give compound 37. Compound 37 is reacted
with an appropriate mannich base, such as
N-methyl-N-methylenemethanaminium iodide, in an appropriate solvent, such
as acetonitrile, to afford compound 12. Compound 12 is reacted with an
appropriate methylating agent, such as methyl iodide, in an appropriate
solvent, such as diethyl ether, to give compound 13.

[0162] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme VII, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R16-R17, R19, and
R21-R22, compound 35 with the corresponding deuterium
substitutions can be used. To introduce deuterium at one or more
positions of R23-R29, compound 36 with the corresponding
deuterium substitutions can be used.

##STR00017##

[0163] Compound 38 is reacted with an appropriate reducing agent, such as
sodium borohydride, in an appropriate solvent, such as ethanol, to give
compound 39 of Formula I having predominantly (˜4:1) alpha
stereochemistry. The alpha stereoisomer can be further enriched by
recrystallization from an appropriate solvent, such as ethanol.

[0164] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme I, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R1-R17, R99, and
R21-R29, compound 38 with the corresponding deuterium
substitutions can be used. To introduce deuterium at R18, sodium
borodeuteride can be used.

[0165] Deuterium can be incorporated to various positions having an
exchangeable proton, such as the hydroxyl O--H, via proton-deuterium
equilibrium exchange. For example, to introduce deuterium at R20,
this proton may be replaced with deuterium selectively or non-selectively
through a proton-deuterium exchange method known in the art.

##STR00018##

[0166] Compound 38 is reacted with an appropriate reducing agent, such as
potassium tri-sec-butyl borohydride (K-selectride), in an appropriate
solvent, such as tetrahydrofuran, to give compound 40 of Formula I having
beta stereochemistry.

[0167] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme I, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R1-R17, R99, and
R21-R29, compound 38 with the corresponding deuterium
substitutions can be used. To introduce deuterium at R18, potassium
tri-sec-butyl borodeuteride can be used.

[0168] Deuterium can be incorporated to various positions having an
exchangeable proton, such as the hydroxyl O--H, via proton-deuterium
equilibrium exchange. For example, to introduce deuterium at R20,
this proton may be replaced with deuterium selectively or non-selectively
through a proton-deuterium exchange method known in the art.

##STR00019##

[0169] Compound 40 is reacted with compound 41 (wherein P.G. is an
appropriate protecting group, such as carboxybenzoyl) in the presence of
an appropriate coupling agent, such as dicyclohexylcarbodiimide (DCC), an
appropriate catalyst, such as 4-dimethylaminopyridine (DMAP), in an
appropriate solvent, such as dichloromethane, to give compound 42.
Compound 42 is reacted with an appropriate deprotecting agent, such as a
combination of hydrogen and an appropriate catalyst, such as palladium on
carbon, in an appropriate solvent, such as methanol, to give compound 43
of Formula I.

[0170] Deuterium can be incorporated to different positions synthetically,
according to the synthetic procedures as shown in Scheme I, by using
appropriate deuterated intermediates. For example, to introduce deuterium
at one or more positions of R1-R19 and R21-R29,
compound 40 with the corresponding deuterium substitutions can be used.
To introduce deuterium at one or more positions of R30-R37,
compound 41 with the corresponding deuterium substitutions can be used.

[0171] Deuterium can be incorporated to various positions having an
exchangeable proton, such as the hydroxyl O--H or amine N--Hs, via
proton-deuterium equilibrium exchange. For example, to introduce
deuterium at R20 and R38-R39, these protons may be
replaced with deuterium selectively or non-selectively through a
proton-deuterium exchange method known in the art.

[0172] The invention is further illustrated by the following examples. All
IUPAC names were generated using CambridgeSoft's ChemDraw 10.0.

[0173] The following compounds can generally be made using the methods
described above. It is expected that these compounds when made will have
activity similar to those described in the examples above.

[0174] Changes in the metabolic properties of the compounds disclosed
herein as compared to their non-isotopically enriched analogs can be
shown using the following assays. Compounds listed above which have not
yet been made and/or tested are predicted to have changed metabolic
properties as shown by one or more of these assays as well.

Biological Activity Assays

In Vitro Human Liver Microsomal Stability Assay

[0175] Test compounds are dissolved in 50% acetonitrile/50% H2O for
further dilution into the assay. Test compounds were combined with
microsomes obtained from livers of the indicated species in the presence
of a NADPH regenerating system (NRS) for incubation at 37° C. in
duplicate. For non-deuterated test compounds, the internal standard was
the deuterated analog. For deuterated test compounds, the internal
standard was the non-deuterated form. Samples were stored at -70°
C. for subsequent LC/MS/MS analysis.

[0176] The test compounds are incubated at a concentration of 0.25 μM
with 4 mg/mL human liver microsomes for 60 minutes with samples taken at
0, 15, 30, 45 and 60 minutes. At each time point, the reaction is
terminated with the addition of 100 μL acetonitrile containing
internal standard. After vortexing, samples are centrifuged for 10
minutes at 14,000 rpm (RT) and the supernatants transferred to HPLC vials
for LC/MS/MS analysis.

[0178] After chromatographic separation of the analytes, quantitation is
performed using a 4000 QTrap ABI MS/MS detector in positive multiple
reaction monitoring (MRM) mode.

[0179] Noncompartmental pharmacokinetic analyses is carried out using
WinNonlin Professional (version 5.2, Pharsight, Mountain View, Calif.)
and the terminal half life (t1/2) calculated.

In Vitro Human S9 Liver Fraction Assay

[0180] Test compounds are dissolved in 50% acetonitrile/50% H2O for
further dilution into the assay. Test compounds are combined with S9
liver fraction or liver cytosol in the presence of a NADPH regenerating
system (NRS) for incubation at 37° C. in duplicate as noted above
for 60 minutes. For non-deuterated test compounds, the internal standard
is the deuterated analog. For deuterated test compounds, the internal
standard is the non-deuterated form. Samples are stored at -70° C.
for subsequent LC/MS/MS analysis.

[0181] The test compounds are incubated at a concentration of 0.25 μM
with 4 mg/mL human S9 liver fraction for 60 minutes with samples taken at
0, 15, 30, 45 and 60 minutes. At each time point, the reaction is
terminated with the addition of 100 μL acetonitrile containing
internal standard. After vortexing, samples are centrifuged for 10
minutes at 14,000 rpm (RT) and the supernatants transferred to HPLC vials
for LC/MS/MS analysis.

[0185] After chromatographic separation of the analytes, quantitation is
performed using a 4000 QTrap ABI MS/MS detector in positive multiple
reaction monitoring (MRM) mode. The MRM transition parameters for each
analyte and the internal standard are summarized below.

[0186] Noncompartmental pharmacokinetic analyses are carried out using
WinNonlin Professional (version 5.2, Pharsight, Mountain View, Calif.)
and the terminal half life (t1/2) calculated.

In Vitro Metabolism Using Human Cytochrome P450 Enzymes

[0187] Test compounds are dissolved in 50% acetonitrile/50% H2O for
further dilution into the assay. Test compounds at a final concentration
of 0.25 μM are combined with recombinant human CYP1A2, CYP3A4 or
CYP2D6 in microsomes obtained from Baculovirus infected insect cells
(Supersomes®, Gentest, Woburn, Mass.) in the presences of a NADPH
regenerating system (NRS) for incubation at 37° C. for 0, 15, 30,
45 or 60 minutes. The concentrations of CYP isozymes ranges between 25 to
200 pmol/mL. At each time point, the reaction is terminated with the
addition of 100 μL ACN containing an internal standard. For deuterated
test compounds, the internal standard is the non-deuterated form. After
vortexing, samples are centrifuged for 10 minutes at 14,000 rpm (room
temperature) and the supernatants are transferred to HPLC vials for
LC/MS/MS analysis. Samples are stored at -70° C. for subsequent
LC/MS/MS analysis.

[0190] After chromatographic separation of the analytes, quantitation is
performed using a 4000 QTrap ABI MS/MS detector in positive multiple
reaction monitoring (MRM) mode.

Monoamine Oxidase A Inhibition and Oxidative Turnover

[0191] The procedure is carried out using the methods described by Weyler,
Journal of Biological Chemistry 1985, 260, 13199-13207, which is hereby
incorporated by reference in its entirety. Monoamine oxidase A activity
is measured spectrophotometrically by monitoring the increase in
absorbance at 314 nm on oxidation of kynuramine with formation of
4-hydroxyquinoline. The measurements are carried out, at 30° C.,
in 50 mM NaPi buffer, pH 7.2, containing 0.2% Triton X-100
(monoamine oxidase assay buffer), plus 1 mM kynuramine, and the desired
amount of enzyme in 1 mL total volume.

Monooamine Oxidase B Inhibition and Oxidative Turnover

[0192] The procedure is carried out as described in Uebelhack,
Pharmacopsychiatry 1998, 31(5), 187-192, which is hereby incorporated by
reference in its entirety.

Determination of Tetrabenazine and an Active Metabolite by HPLC

[0193] The procedure is carried out as described in Roberts et al.,
Journal of Chromatography, Biomedical Applications 1981, 226(1), 175-82,
which is hereby incorporated by reference in its entirety.

Pharmacokinetic Assays of Tetrabenazine and its Major Metabolite in Man
and Rat

[0194] The procedure is carried out as described in Mehvar, et al., Drug
Metabolism and Disposition 1987, 15(2), 250-5, which is hereby
incorporated by reference in its entirety.

Detecting Tetrabenazine Metabolites in Animals and Man

[0195] The procedure is carried out as described in Schwartz, et al.,
Biochemical Pharmacology 1966, 15(5), 645-55, which is hereby
incorporated by reference in its entirety.

Mass Spectrometric Determination of Tetrabenazine

[0196] The procedure is carried out as described in Jindal, et al.,
Journal of Chromatography, Biomedical Applications 1989, 493(2), 392-7,
which is hereby incorporated by reference in its entirety.

In Vitro Radioligand Binding Assay

[0197] The procedure is carried out as described in Scherman et al.,
Journal of Neurochemistry 1988, 50(4), 1131-36, which is hereby
incorporated by reference in its entirety.

In Vitro Radioligand Binding Assay

[0198] The procedure is carried out as described in Kilboum et al.,
Synapse 2002, 43(3), 188-194, which is hereby incorporated by reference
in its entirety.

In Vitro Radioligand Binding Assay

[0199] The procedure is carried out as described in Kilboum et al.,
European Journal of Pharmacology 1997, 331(2-3), 161-68, which is hereby
incorporated by reference in its entirety.

3H-Histamine Transport Assay

[0200] The procedure is carried out as described in Erickson et al.,
Journal of Molecular Neuroscience 1995, 6(4), 277-87, which is hereby
incorporated by reference in its entirety.

Pharmacokinetic Evaluation in Rat and Dog

[0201] The procedure is carried out as described in U.S. Pat. No.
8,039,627, which is hereby incorporated by reference in its entirety.

VMAT2 Binding Assay

[0202] The procedure is carried out as described in U.S. Pat. No.
8,039,627, which is hereby incorporated by reference in its entirety.

Receptor Selectivity Binding Assays

[0203] The procedure is carried out as described in U.S. Pat. No.
8,039,627, which is hereby incorporated by reference in its entirety.

VMAT2 Inhibitor-Induced Reductions in Locomotor Activity

[0204] The procedure is carried out as described in U.S. Pat. No.
8,039,627, which is hereby incorporated by reference in its entirety.

VMAT2 Inhibitor-Induced Ptosis Assay

[0205] The procedure is carried out as described in U.S. Pat. No.
8,039,627, which is hereby incorporated by reference in its entirety.

[0206] From the foregoing description, one skilled in the art can easily
ascertain the essential characteristics of this invention, and without
departing from the spirit and scope thereof, can make various changes and
modifications of the invention to adapt it to various usages and
conditions.

Patent applications in class Ring nitrogen is shared by two of the cyclos

Patent applications in all subclasses Ring nitrogen is shared by two of the cyclos